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Genes Nov 2023Dementia is a syndrome of global and progressive deterioration of cognitive skills, especially memory, learning, abstract thinking, and orientation, usually affecting... (Review)
Review
Dementia is a syndrome of global and progressive deterioration of cognitive skills, especially memory, learning, abstract thinking, and orientation, usually affecting the elderly. The most common forms are Alzheimer's disease, vascular dementia, and other (frontotemporal, Lewy body disease) dementias. The etiology of these multifactorial disorders involves complex interactions of various environmental and (epi)genetic factors and requires multiple forms of pharmacological intervention, including anti-dementia drugs for cognitive impairment, antidepressants, antipsychotics, anxiolytics and sedatives for behavioral and psychological symptoms of dementia, and other drugs for comorbid disorders. The pharmacotherapy of dementia patients has been characterized by a significant interindividual variability in drug response and the development of adverse drug effects. The therapeutic response to currently available drugs is partially effective in only some individuals, with side effects, drug interactions, intolerance, and non-compliance occurring in the majority of dementia patients. Therefore, understanding the genetic basis of a patient's response to pharmacotherapy might help clinicians select the most effective treatment for dementia while minimizing the likelihood of adverse reactions and drug interactions. Recent advances in pharmacogenomics may contribute to the individualization and optimization of dementia pharmacotherapy by increasing its efficacy and safety via a prediction of clinical outcomes. Thus, it can significantly improve the quality of life in dementia patients.
Topics: Humans; Aged; Pharmacogenetics; Quality of Life; Alzheimer Disease; Antidepressive Agents; Cognition
PubMed: 38002991
DOI: 10.3390/genes14112048 -
Pharmacological Research Feb 2024Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has received much attention for its rapid antidepressant effects. A single administration... (Review)
Review
Ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, has received much attention for its rapid antidepressant effects. A single administration of ketamine elicits rapid and sustained antidepressant effects in both humans and animals. Current efforts are focused on uncovering molecular mechanisms responsible for ketamine's antidepressant activity. Ketamine primarily acts via the glutamatergic pathway, and increasing evidence suggests that ketamine induces synaptic and structural plasticity through increased translation and release of neurotrophic factors, activation of mammalian target of rapamycin (mTOR), and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-mediated synaptic potentiation. However, the initial events triggering activation of intracellular signaling cascades and the mechanisms responsible for the sustained antidepressant effects of ketamine remain poorly understood. Over the last few years, it has become apparent that in addition to the fast actions of the ligand-gated AMPARs and NMDARs, metabotropic glutamate receptors (mGluRs), and particularly mGluR5, may also play a role in the antidepressant action of ketamine. Although research on mGluR5 in relation to the beneficial actions of ketamine is still in its infancy, a careful evaluation of the existing literature can identify converging trends and provide new interpretations. Here, we review the current literature on mGluR5 regulation in response to ketamine from a molecular perspective and propose a possible mechanism linking NMDAR inhibition to mGluR5 modulation.
Topics: Humans; Animals; Ketamine; Depression; Antidepressive Agents; Receptors, N-Methyl-D-Aspartate; Brain-Derived Neurotrophic Factor; Mammals
PubMed: 38278430
DOI: 10.1016/j.phrs.2024.107081 -
International Journal of Molecular... Jul 2023About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely...
About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.
Topics: Animals; Mice; Analgesics, Opioid; Mianserin; Venlafaxine Hydrochloride; Fluvoxamine; Mirtazapine; Fluoxetine; Reboxetine; Trazodone; Moclobemide; Depression; Antidepressive Agents; Naloxone; Dose-Response Relationship, Drug
PubMed: 37446323
DOI: 10.3390/ijms241311142 -
Biomedicine & Pharmacotherapy =... Sep 2023TREK-1 (TWIK-related potassium channel-1) is a subunit of the two-pore domain potassium (K2p) channel and is widely expressed in the brain. TREK-1 knockout mice were...
TREK-1 (TWIK-related potassium channel-1) is a subunit of the two-pore domain potassium (K2p) channel and is widely expressed in the brain. TREK-1 knockout mice were shown to have antidepressant-like effects, providing evidence for the channel's potential as a therapeutic target. However, currently there is no good pharmacological inhibitor specifically targeting TREK-1 containing K2p channels that also displays similar antidepressant-like effects. Here, we sought to find selective and potent inhibitors for TREK-1 related dimers both in vitro and in vivo. We synthesized and evaluated 2-hydroxy-3-phenoxypropyl piperidine derivatives yielding a library from which many TREK-1 targeting candidates emerged. Among these, hydroxyl-phenyl- (2a), piperidino- (2g), and pyrrolidino- (2h) piperidinyl substituted compounds showed high potencies to TREK-1 homodimers with significant antidepressant-like effects in forced swim test and tail suspension test. Interestingly, these compounds were found to have high potencies to TWIK-1/TREK-1 heterodimers. Contrastingly, difluoropiperidinyl-4-fluorophenoxy (3e) and 4-hydroxyphenyl-piperidinyl-4-fluorophenoxy (3j) compounds had high potencies to TREK-1 homodimer but lower potency to TWIK-1/TREK-1 heterodimers without significant antidepressant-like effects. We observed positive correlation between inhibition potency to TWIK-1/TREK-1 and immobility time, and no correlation between inhibition potency to TREK-1 homodimer and immobility time. This was consistent with molecular docking simulations of selected compounds to TREK-1 homodimeric and TWIK-1/TREK-1 heterodimeric models. Existing antidepressant fluoxetine was also found to potently inhibit TWIK-1/TREK-1 heterodimers. Our study reveals novel potent TWIK-1/TREK-1 inhibitors 2a, 2g, and 2h as potential antidepressants and suggest that the TWIK-1/TREK-1 heterodimer could be a potential novel molecular therapeutic target for antidepressants.
Topics: Mice; Animals; Molecular Docking Simulation; Potassium Channels, Tandem Pore Domain; Brain; Antidepressive Agents; Mice, Knockout
PubMed: 37454597
DOI: 10.1016/j.biopha.2023.115139 -
The British Journal of General Practice... Jul 2024Many patients with depressive disorders use antidepressants longer than clinically indicated. Long-term use of antidepressants is associated with high individual and...
BACKGROUND
Many patients with depressive disorders use antidepressants longer than clinically indicated. Long-term use of antidepressants is associated with high individual and societal costs. Patients often perceive antidepressant discontinuation as challenging.
AIM
To understand patients' expectations about discontinuation, to document their experiences with long-term use and discontinuation, and to identify factors that can help or hinder discontinuation.
DESIGN AND SETTING
Qualitative study using semi-structured interviews via telephone with adult patients in Germany.
METHOD
We interviewed 32 patients with remitted major depressive disorder and long-term antidepressant use. We analysed transcripts with content analysis aided by MAXQDA to derive thematic categories.
RESULTS
Patients expected to eliminate side effects or regain independence after discontinuation. Such positive expectations were perceived as facilitators and motivated patients' wish to discontinue antidepressants. However, patients also had negative expectations such as recurrence or discontinuation symptoms. Patients' negative expectations were often fuelled by previous negative experiences, which persisted despite a wish to stop antidepressants, and hindered discontinuation. Most patients perceived antidepressants as being effective, but experienced side effects and further problems. Patients felt inadequately informed about treatment duration and methods for discontinuation. Further barriers and facilitators included a stable environment, availability of support, and treatment information.
CONCLUSION
Patients prefer to discontinue antidepressants within structured frameworks that provide information and support. Identified facilitators and barriers may help optimise appropriate use and discontinuation of antidepressants in routine practice. Promoting functional expectations and specifying individualised approaches to minimise dysfunctional expectations, adapted to patients' previous experiences, appear to be especially important.
Topics: Humans; Antidepressive Agents; Male; Female; Qualitative Research; Depressive Disorder, Major; Middle Aged; Adult; Germany; Medication Adherence; Motivation; Aged
PubMed: 38228356
DOI: 10.3399/BJGP.2023.0020 -
Molecular Psychiatry Apr 2024The discovery that subanesthetic doses of (R, S)-ketamine (ketamine) and (S)-ketamine (esketamine) rapidly induce antidepressant effects and promote sustained actions... (Review)
Review
The discovery that subanesthetic doses of (R, S)-ketamine (ketamine) and (S)-ketamine (esketamine) rapidly induce antidepressant effects and promote sustained actions following drug clearance in depressed patients who are treatment-resistant to other therapies has resulted in a paradigm shift in the conceptualization of how rapidly and effectively depression can be treated. Consequently, the mechanism(s) that next generation antidepressants may engage to improve pathophysiology and resultant symptomology are being reconceptualized. Impaired excitatory glutamatergic synapses in mood-regulating circuits are likely a substantial contributor to the pathophysiology of depression. Metaplasticity is the process of regulating future capacity for plasticity by priming neurons with a stimulation that alters later neuronal plasticity responses. Accordingly, the development of treatment modalities that specifically modulate the duration, direction, or magnitude of glutamatergic synaptic plasticity events such as long-term potentiation (LTP), defined here as metaplastogens, may be an effective approach to reverse the pathophysiology underlying depression and improve depression symptoms. We review evidence that the initiating mechanisms of pharmacologically diverse rapid-acting antidepressants (i.e., ketamine mimetics) converge on consistent downstream molecular mediators that facilitate the expression/maintenance of increased synaptic strength and resultant persisting antidepressant effects. Specifically, while the initiating mechanisms of these therapies may differ (e.g., cell type-specificity, N-methyl-D-aspartate receptor (NMDAR) subtype-selective inhibition vs activation, metabotropic glutamate receptor 2/3 antagonism, AMPA receptor potentiation, 5-HT receptor-activating psychedelics, etc.), the sustained therapeutic mechanisms of putative rapid-acting antidepressants will be mediated, in part, by metaplastic effects that converge on consistent molecular mediators to enhance excitatory neurotransmission and altered capacity for synaptic plasticity. We conclude that the convergence of these therapeutic mechanisms provides the opportunity for metaplasticity processes to be harnessed as a druggable plasticity mechanism by next-generation therapeutics. Further, targeting metaplastic mechanisms presents therapeutic advantages including decreased dosing frequency and associated diminished adverse responses by eliminating the requirement for the drug to be continuously present.
Topics: Humans; Antidepressive Agents; Neuronal Plasticity; Ketamine; Animals; Depression; Long-Term Potentiation; Receptors, N-Methyl-D-Aspartate; Synapses
PubMed: 38177353
DOI: 10.1038/s41380-023-02397-1 -
BMC Psychiatry Dec 2023This study included evaluation of the effectiveness of vortioxetine, a treatment for adults with major depressive disorder (MDD), using patient-reported outcome measures...
BACKGROUND
This study included evaluation of the effectiveness of vortioxetine, a treatment for adults with major depressive disorder (MDD), using patient-reported outcome measures (PROMs) in a real-world setting.
METHODS
This retrospective chart review analyzed the care experiences of adult patients with a diagnosis of MDD from Parkview Physicians Group - Mind-Body Medicine, Midwestern United States. Patients with a prescription for vortioxetine, an initial baseline visit, and ≥ 2 follow-up visits within 16 weeks from September 2014 to December 2018 were included. The primary outcome measure was effectiveness of vortioxetine on depression severity as assessed by change in Patient Health Questionnaire-9 (PHQ-9) scores ~ 12 weeks after initiation of vortioxetine. Secondary outcomes included changes in depression-related symptoms (i.e., sexual dysfunction, sleep disturbance, cognitive function, work/social function), clinical characteristics, response, remission, and medication persistence. Clinical narrative notes were also analyzed to examine sleep disturbance, sexual dysfunction, appetite, absenteeism, and presenteeism. All outcomes were examined at index (start of vortioxetine) and at ~ 12 weeks, and mean differences were analyzed using pairwise t tests.
RESULTS
A total of 1242 patients with MDD met inclusion criteria, and 63.9% of these patients had ≥ 3 psychiatric diagnoses and 65.9% were taking ≥ 3 medications. PHQ-9 mean scores decreased significantly from baseline to week 12 (14.15 ± 5.8 to 9.62 ± 6.03, respectively; p < 0.001). At week 12, the response and remission rates in all patients were 31.0% and 23.1%, respectively, and 67% continued vortioxetine treatment. Overall, results also showed significant improvements by week 12 in anxiety (p < 0.001), sexual dysfunction (p < 0.01), sleep disturbance (p < 0.01), cognitive function (p < 0.001), work/social functioning (p = 0.021), and appetite (p < 0.001). A significant decrease in presenteeism was observed at week 12 (p < 0.001); however, no significant change was observed in absenteeism (p = 0.466).
CONCLUSIONS
Using PROMs, our study results suggest that adults with MDD prescribed vortioxetine showed improvement in depressive symptoms in the context of a real-world clinical practice setting. These patients had multiple comorbid psychiatric and physical diagnoses and multiple previous antidepressant treatments had failed.
Topics: Adult; Humans; Vortioxetine; Depressive Disorder, Major; Retrospective Studies; Antidepressive Agents; Sexual Dysfunction, Physiological; Treatment Outcome; Double-Blind Method
PubMed: 38093196
DOI: 10.1186/s12888-023-05439-8 -
Neuroscience Letters May 2024The antidepressant effects of ketamine and esketamine are well-documented. Nonetheless, most of the underlying molecular mechanisms have to be uncovered yet. In the last... (Review)
Review
The antidepressant effects of ketamine and esketamine are well-documented. Nonetheless, most of the underlying molecular mechanisms have to be uncovered yet. In the last decade, metabolomics has emerged as a useful means to investigate the metabolic phenotype associated with depression as well as changes induced by antidepressant treatments. This mini-review aims at summarizing the main findings from preclinical and clinical studies that used metabolomics to investigate the metabolic effects of subanesthetic, antidepressant doses of ketamine and esketamine and their relationship with clinical response. Both animal and human studies report alterations in several metabolic pathways - including the tricarboxylic acid cycle, glycolysis, the pentose phosphate pathway, lipid metabolism, amino acid metabolism, the kynurenine pathway, and the urea cycle - following the administration of ketamine or its enantiomers. Although more research is needed to clarify commonalities and differences in molecular mechanisms of action between the racemic compound and its enantiomers, these findings comprehensively support an influence of ketamine and esketamine on mitochondrial and cellular energy production, membrane homeostasis, neurotransmission, and signaling. Metabolomics may thus represent a promising strategy to clarify molecular mechanisms underlying treatment-resistant depression and related markers of clinical response to ketamine and esketamine. This body of preclinical and clinical evidence, if further substantiated, has the potential to guide clinicians towards personalized approaches, contributing to new paradigms in the clinical management of depression.
Topics: Ketamine; Humans; Antidepressive Agents; Metabolomics; Animals; Depression
PubMed: 38670523
DOI: 10.1016/j.neulet.2024.137791 -
CNS Neuroscience & Therapeutics Apr 2024As a phencyclidine (PCP) analog, ketamine can generate rapid-onset and substantial anesthetic effects. Contrary to traditional anesthetics, ketamine is a dissociative... (Review)
Review
BACKGROUND
As a phencyclidine (PCP) analog, ketamine can generate rapid-onset and substantial anesthetic effects. Contrary to traditional anesthetics, ketamine is a dissociative anesthetic and can induce loss of consciousness in patients. Recently, the subanaesthetic dose of ketamine was found to produce rapid-onset and lasting antidepressant effects.
AIM
However, how different concentrations of ketamine can induce diverse actions remains unclear. Furthermore, the molecular mechanisms underlying the NMDAR-mediated anesthetic and antidepressant effects of ketamine are not fully understood.
METHOD
In this review, we have introduced ketamine and its metabolism, summarized recent advances in the molecular mechanisms underlying NMDAR inhibition in the anesthetic and antidepressant effects of ketamine, explored the possible functions of NMDAR subunits in the effects of ketamine, and discussed the future directions of ketamine-based anesthetic and antidepressant drugs.
RESULT
Both the anesthetic and antidepressant effects of ketamine were thought to be mediated by N-methyl-D-aspartate receptor (NMDAR) inhibition.
CONCLUSION
The roles of NMDARs have been extensively studied in the anaesthetic effects of ketamine. However, the roles of NMDARs in antidepressant effects of ketamine are complicated and controversial.
Topics: Humans; Ketamine; Receptors, N-Methyl-D-Aspartate; Antidepressive Agents; Anesthetics
PubMed: 37680076
DOI: 10.1111/cns.14464 -
Scientific Reports Aug 2023The objective of this study was to assess the benefits and potential risks associated with different physical exercise modalities for managing symptoms in adults with... (Meta-Analysis)
Meta-Analysis
The objective of this study was to assess the benefits and potential risks associated with different physical exercise modalities for managing symptoms in adults with major depressive disorder who were not receiving second-generation antidepressants or cognitive behavioral therapy. A systematic review and meta-analysis of randomized controlled trials (RCTs) were conducted. The search included multiple databases: Medline, Cochrane Central Register of Controlled Trials (CENTRAL), Embase, PsycInfo, Web of Science, Clinical Trials repository, gray literature, and manual search. No language restrictions were applied. Eligible studies involved RCTs of adults with major depressive disorder who were not on antidepressants or receiving psychological therapy, comparing various exercise modalities with second-generation antidepressants or cognitive behavioral therapy, body-mind exercise, or no exercise interventions. Nine RCTs involving 678 adults were analyzed. The pooled results indicated a small clinical effect favoring exercise in reducing depressive symptoms, although the difference was not statistically significant (SMD = 0.27, 95% CI [- 0.58, 0.04], P = 0.09). Subgroup analyses suggested that intervention duration, frequency, intensity, supervision, age, overweight/obesity status, and diagnosis of depression could influence treatment outcomes. A sensitivity analysis was conducted for studies with controls without exercise interventions and a low risk of bias in the domains related to the randomization process and deviations from the intended interventions. The results showed that there are no statistically significant differences when interventions are compared with medication and body-mind exercise (p = 0.12, I = 78%). Furthermore, the analysis showed a moderate effect size favoring exercise, but no statistically significant difference between groups (p = 0.05), with high heterogeneity (I = 85%). The evidence quality was generally low to very low, and methodological limitations compromised the certainty of the findings. Adverse events associated with exercise were manageable. The study emphasizes the need for well-designed RCTs to provide clearer insights into the potential benefits of exercise in managing major depressive disorder symptoms. Caution is warranted in interpreting these results due to the limitations of the included studies.Systematic review registration: PROSPERO CRD42022356741.
Topics: Adult; Humans; Depressive Disorder, Major; Antidepressive Agents; Cognitive Behavioral Therapy; Antidepressive Agents, Second-Generation; Exercise
PubMed: 37580497
DOI: 10.1038/s41598-023-39783-2